Publications by authors named "Edward Yu"

206 Publications

Scalable, highly stable Si-based metal-insulator-semiconductor photoanodes for water oxidation fabricated using thin-film reactions and electrodeposition.

Nat Commun 2021 Jun 25;12(1):3982. Epub 2021 Jun 25.

Microelectronics Research Center, University of Texas, Austin, TX, USA.

Metal-insulator-semiconductor (MIS) structures are widely used in Si-based solar water-splitting photoelectrodes to protect the Si layer from corrosion. Typically, there is a tradeoff between efficiency and stability when optimizing insulator thickness. Moreover, lithographic patterning is often required for fabricating MIS photoelectrodes. In this study, we demonstrate improved Si-based MIS photoanodes with thick insulating layers fabricated using thin-film reactions to create localized conduction paths through the insulator and electrodeposition to form metal catalyst islands. These fabrication approaches are low-cost and highly scalable, and yield MIS photoanodes with low onset potential, high saturation current density, and excellent stability. By combining this approach with a pn-Si buried junction, further improved oxygen evolution reaction (OER) performance is achieved with an onset potential of 0.7 V versus reversible hydrogen electrode (RHE) and saturation current density of 32 mA/cm under simulated AM1.5G illumination. Moreover, in stability testing in 1 M KOH aqueous solution, a constant photocurrent density of ~22 mA/cm is maintained at 1.3 V versus RHE for 7 days.
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http://dx.doi.org/10.1038/s41467-021-24229-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233328PMC
June 2021

Guillain-Barré Syndrome after Novel Coronavirus Disease 2019.

J Emerg Med 2021 Mar 26. Epub 2021 Mar 26.

Department of Neurology, Staten Island University Hospital, Staten Island, New York; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.

Background: Novel coronavirus disease 2019 (COVID-19) has affected more than 89 million people worldwide. As the pandemic rages on, more complications of the disease are being recognized, including stroke, cardiovascular disease, thromboembolic events, encephalopathy, seizures, and more. Peripheral nervous system involvement, particularly Guillain-Barré syndrome (GBS), is of special interest, given the increasing reports of cases related to COVID-19. Because of the potentially delayed onset of symptoms of polyradiculoneuropathy and weakness after the traditional COVID-19 symptoms, it is vitally important for emergency physicians to be vigilant and to consider GBS as part of their differential diagnosis. GBS usually occurs after an infectious insult, and a variety of culprit pathogens have been identified in the literature.

Case Report: We describe the case of a 35-year-old man who developed GBS after being diagnosed with COVID-19 infection. The patient displayed classic symptoms of neuropathy, areflexia, and lower extremity weakness. Cerebrospinal fluid evaluation demonstrated albuminocytologic dissociation seen in GBS, although anti-ganglioside autoantibodies were negative. These antibodies are often negative and do not exclude the diagnosis. The patient responded clinically to intravenous immunoglobulin therapy and was discharged home. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case report contributes further evidence that COVID-19 joins other organisms as causes of GBS. Emergency physicians are the first point of contact for many patients. Increased awareness of this complication of COVID-19 will lead to higher detection. Prompt recognition could lead to speedier and more complete neurologic recovery of affected patients.
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http://dx.doi.org/10.1016/j.jemermed.2021.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997391PMC
March 2021

Cryo-EM Determination of Eravacycline-Bound Structures of the Ribosome and the Multidrug Efflux Pump AdeJ of Acinetobacter baumannii.

mBio 2021 06 28;12(3):e0103121. Epub 2021 May 28.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Antibiotic-resistant strains of the Gram-negative pathogen Acinetobacter baumannii have emerged as a significant global health threat. One successful therapeutic option to treat bacterial infections has been to target the bacterial ribosome. However, in many cases, multidrug efflux pumps within the bacterium recognize and extrude these clinically important antibiotics designed to inhibit the protein synthesis function of the bacterial ribosome. Thus, multidrug efflux within A. baumannii and other highly drug-resistant strains is a major cause of failure of drug-based treatments of infectious diseases. We here report the first structures of the cinetobacter rug fflux (Ade)J pump in the presence of the antibiotic eravacycline, using single-particle cryo-electron microscopy (cryo-EM). We also describe cryo-EM structures of the eravacycline-bound forms of the A. baumannii ribosome, including the 70S, 50S, and 30S forms. Our data indicate that the AdeJ pump primarily uses hydrophobic interactions to bind eravacycline, while the 70S ribosome utilizes electrostatic interactions to bind this drug. Our work here highlights how an antibiotic can bind multiple bacterial targets through different mechanisms and potentially enables drug optimization by taking advantage of these different modes of ligand binding. Acinetobacter baumannii has developed into a highly antibiotic-resistant Gram-negative pathogen. The prevalent AdeJ multidrug efflux pump mediates resistance to different classes of antibiotics known to inhibit the function of the 70S ribosome. Here, we report the first structures of the A. baumannii AdeJ pump, both in the absence and presence of eravacycline. We also describe structures of the A. baumannii ribosome bound by this antibiotic. Our results indicate that AdeJ and the ribosome use very distinct binding modes for drug recognition. Our work will ultimately enable structure-based drug discovery to combat antibiotic-resistant A. baumannii infection.
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http://dx.doi.org/10.1128/mBio.01031-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263017PMC
June 2021

Contralateral Breast Cancer With Multiple Primary Neoplasms in a Patient With Neurofibromatosis Type 1: A Case Report and Review of the Literature.

Cureus 2021 Mar 6;13(3):e13738. Epub 2021 Mar 6.

Radiation Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, CAN.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neuroectodermal disorder associated with increased risk for several neural and non-neural malignancies. The link between NF1 and breast cancer has recently been established, with patients with NF1 being at higher risk for developing breast cancer, more likely to get breast cancer at a younger age, and more likely to have their breast cancer present with more adverse prognostic factors. Although rare, several cases of NF1 patients with contralateral breast cancer have been mentioned in the literature. We report the case of one such patient who developed contralateral breast cancer 40 years after her initial breast cancer diagnosis.
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http://dx.doi.org/10.7759/cureus.13738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020820PMC
March 2021

Cryo-EM Structures of CusA Reveal a Mechanism of Metal-Ion Export.

mBio 2021 04 5;12(2). Epub 2021 Apr 5.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Gram-negative bacteria utilize the resistance-nodulation-cell division (RND) superfamily of efflux pumps to expel a variety of toxic compounds from the cell. The CusA membrane protein, which recognizes and extrudes biocidal Cu(I) and Ag(I) ions, belongs to the heavy-metal efflux (HME) subfamily of RND efflux pumps. We here report four structures of the trimeric CusA heavy-metal efflux pump in the presence of Cu(I) using single-particle cryo-electron microscopy (cryo-EM). We discover that different CusA protomers within the trimer are able to bind Cu(I) ions simultaneously. Our structural data combined with molecular dynamics (MD) simulations allow us to propose a mechanism for ion transport where each CusA protomer functions independently within the trimer. The bacterial RND superfamily of efflux pumps mediate resistance to a variety of biocides, including Cu(I) and Ag(I) ions. Here we report four cryo-EM structures of the trimeric CusA pump in the presence of Cu(I). Combined with MD simulations, our data indicate that each CusA protomer within the trimer recognizes and extrudes Cu(I) independently.
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http://dx.doi.org/10.1128/mBio.00452-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092243PMC
April 2021

Cryo-EM as a tool to study bacterial efflux systems and the membrane proteome.

Fac Rev 2021 1;10:24. Epub 2021 Mar 1.

Department of Pharmacology, Case Western Reserve University School of Medicine, 2109 Adelbert Rd, Cleveland, OH 44106-4965, USA.

Antibiotic resistance is an emerging threat to global health. Current treatment regimens for these types of bacterial infections are becoming increasingly inadequate. Thus, new innovative technologies are needed to help identify and characterize novel drugs and drug targets which are critical in order to combat multidrug-resistant bacterial strains. Bacterial efflux systems have emerged as an attractive target for drug design, as blocking their export function significantly increases the potency of administered antibiotics. However, in order to develop potent and tolerable efflux pump inhibitors with high efficacy, detailed structural information is required for both the apo- and substrate-bound forms of these membrane proteins. The emergence of cryo-electron microscopy (cryo-EM) has greatly advanced the field of membrane protein structural biology. It has significantly enhanced the ability to solve large multi-protein complexes as well as extract meaningful data from a heterogeneous sample, such as identification of several assembly states of the bacterial ribosome, from a single data set. This technique can be expanded to solve the structures of substrate-bound efflux pumps and entire efflux systems from previously unusable membrane protein sample preparations. Subsequently, cryo-EM combined with other biophysical techniques has the potential to markedly advance the field of membrane protein structural biology. The ability to discern complete transport machineries, enzymatic signal transduction pathways, and other membrane-associated complexes will help us fully understand the complexities of the membrane proteome.
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http://dx.doi.org/10.12703/r/10-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946387PMC
March 2021

Cryoelectron Microscopy Structures of AdeB Illuminate Mechanisms of Simultaneous Binding and Exporting of Substrates.

mBio 2021 02 23;12(1). Epub 2021 Feb 23.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

is a Gram-negative pathogen that has emerged as one of the most highly antibiotic-resistant bacteria worldwide. Multidrug efflux within these highly drug-resistant strains and other opportunistic pathogens is a major cause of failure of drug-based treatments of infectious diseases. The best-characterized multidrug efflux system in is the prevalent rug fflux B (AdeB) pump, which is a member of the resistance-nodulation-cell division (RND) superfamily. Here, we report six structures of the trimeric AdeB multidrug efflux pump in the presence of ethidium bromide using single-particle cryoelectron microscopy (cryo-EM). These structures allow us to directly observe various novel conformational states of the AdeB trimer, including the transmembrane region of trimeric AdeB can be associated with form a trimer assembly or dissociated into "dimer plus monomer" and "monomer plus monomer plus monomer" configurations. We also discover that a single AdeB protomer can simultaneously anchor a number of ethidium ligands and that different AdeB protomers can bind ethidium molecules simultaneously. Combined with molecular dynamics (MD) simulations, we reveal a drug transport mechanism that involves multiple multidrug-binding sites and various transient states of the AdeB membrane protein. Our data suggest that each AdeB protomer within the trimer binds and exports drugs independently. has emerged as one of the most highly antibiotic-resistant Gram-negative pathogens. The prevalent AdeB multidrug efflux pump mediates resistance to a broad spectrum of clinically relevant antimicrobial agents. Here, we report six cryo-EM structures of the trimeric AdeB pump in the presence of ethidium bromide. We discover that a single AdeB protomer can simultaneously anchor a number of ligands, and different AdeB protomers can bind ethidium molecules simultaneously. The results indicate that each AdeB protomer within the trimer recognizes and extrudes drugs independently.
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http://dx.doi.org/10.1128/mBio.03690-20DOI Listing
February 2021

Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT.

EMBO Rep 2021 03 20;22(3):e51628. Epub 2021 Jan 20.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate-nitrite transporter (PfFNT), a 34-kDa transmembrane protein, has been identified as a novel drug target as it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol. The structure and detailed molecular mechanism of this membrane protein are not yet available. Here we present structures of PfFNT in the absence and presence of the functional inhibitor MMV007839 at resolutions of 2.56 Å and 2.78 Å using single-particle cryo-electron microscopy. Genetic analysis and transport assay indicate that PfFNT is able to transfer lactate across the membrane. Combined, our data suggest a stepwise displacement mechanism for substrate transport. The PfFNT membrane protein is capable of picking up lactate ions from the parasite's cytosol, converting them to lactic acids and then exporting these acids into the extracellular space.
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http://dx.doi.org/10.15252/embr.202051628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926216PMC
March 2021

A 'Build and Retrieve' methodology to simultaneously solve cryo-EM structures of membrane proteins.

Nat Methods 2021 01 6;18(1):69-75. Epub 2021 Jan 6.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Single-particle cryo-electron microscopy (cryo-EM) has become a powerful technique in the field of structural biology. However, the inability to reliably produce pure, homogeneous membrane protein samples hampers the progress of their structural determination. Here, we develop a bottom-up iterative method, Build and Retrieve (BaR), that enables the identification and determination of cryo-EM structures of a variety of inner and outer membrane proteins, including membrane protein complexes of different sizes and dimensions, from a heterogeneous, impure protein sample. We also use the BaR methodology to elucidate structural information from Escherichia coli K12 crude membrane and raw lysate. The findings demonstrate that it is possible to solve high-resolution structures of a number of relatively small (<100 kDa) and less abundant (<10%) unidentified membrane proteins within a single, heterogeneous sample. Importantly, these results highlight the potential of cryo-EM for systems structural proteomics.
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http://dx.doi.org/10.1038/s41592-020-01021-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808410PMC
January 2021

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids.

PLoS Pathog 2020 12 8;16(12):e1009119. Epub 2020 Dec 8.

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, United States of America.

Infections caused by Gram-negative bacteria are difficult to fight because these pathogens exclude or expel many clinical antibiotics and host defense molecules. However, mammals have evolved a substantial immune arsenal that weakens pathogen defenses, suggesting the feasibility of developing therapies that work in concert with innate immunity to kill Gram-negative bacteria. Using chemical genetics, we recently identified a small molecule, JD1, that kills Salmonella enterica serovar Typhimurium (S. Typhimurium) residing within macrophages. JD1 is not antibacterial in standard microbiological media, but rapidly inhibits growth and curtails bacterial survival under broth conditions that compromise the outer membrane or reduce efflux pump activity. Using a combination of cellular indicators and super resolution microscopy, we found that JD1 damaged bacterial cytoplasmic membranes by increasing fluidity, disrupting barrier function, and causing the formation of membrane distortions. We quantified macrophage cell membrane integrity and mitochondrial membrane potential and found that disruption of eukaryotic cell membranes required approximately 30-fold more JD1 than was needed to kill bacteria in macrophages. Moreover, JD1 preferentially damaged liposomes with compositions similar to E. coli inner membranes versus mammalian cell membranes. Cholesterol, a component of mammalian cell membranes, was protective in the presence of neutral lipids. In mice, intraperitoneal administration of JD1 reduced tissue colonization by S. Typhimurium. These observations indicate that during infection, JD1 gains access to and disrupts the cytoplasmic membrane of Gram-negative bacteria, and that neutral lipids and cholesterol protect mammalian membranes from JD1-mediated damage. Thus, it may be possible to develop therapeutics that exploit host innate immunity to gain access to Gram-negative bacteria and then preferentially damage the bacterial cell membrane over host membranes.
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http://dx.doi.org/10.1371/journal.ppat.1009119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748285PMC
December 2020

Structural and Functional Diversity of Resistance-Nodulation-Cell Division Transporters.

Chem Rev 2021 May 19;121(9):5378-5416. Epub 2020 Nov 19.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.

Multidrug resistant (MDR) bacteria are a global threat with many common infections becoming increasingly difficult to eliminate. While significant effort has gone into the development of potent biocides, the effectiveness of many first-line antibiotics has been diminished due to adaptive resistance mechanisms. Bacterial membrane proteins belonging to the resistance-nodulation-cell division (RND) superfamily play significant roles in mediating bacterial resistance to antimicrobials. They participate in multidrug efflux and cell wall biogenesis to transform bacterial pathogens into "superbugs" that are resistant even to last resort antibiotics. In this review, we summarize the RND superfamily of efflux transporters with a primary focus on the assembly and function of the inner membrane pumps. These pumps are critical for extrusion of antibiotics from the cell as well as the transport of lipid moieties to the outer membrane to establish membrane rigidity and stability. We analyze recently solved structures of bacterial inner membrane efflux pumps as to how they bind and transport their substrates. Our cumulative data indicate that these RND membrane proteins are able to utilize different oligomerization states to achieve particular activities, including forming MDR pumps and cell wall remodeling machineries, to ensure bacterial survival. This mechanistic insight, combined with simulated docking techniques, allows for the design and optimization of new efflux pump inhibitors to more effectively treat infections that today are difficult or impossible to cure.
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http://dx.doi.org/10.1021/acs.chemrev.0c00621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119314PMC
May 2021

Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

Breast Cancer Res Treat 2020 Sep 6;183(2):365-372. Epub 2020 Jul 6.

Department of Medicine, Division of Clinical Pharmacology, Western University, London, ON, Canada.

Purpose: Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer.

Methods: One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia.

Results: More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia.

Conclusions: Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.
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http://dx.doi.org/10.1007/s10549-020-05777-1DOI Listing
September 2020

Zeta Potential Dependent Self-Assembly for Very Large Area Nanosphere Lithography.

Nano Lett 2020 07 2;20(7):5090-5096. Epub 2020 Jun 2.

Department of Electrical and Computer Engineering, The University of Texas at Austin, 10100 Burnet Road, Building 160, Austin, Texas 78758, United States.

Nanosphere lithography offers a rapid, low-cost approach for patterning of large-area two-dimensional periodic nanostructures. However, a complete understanding of the nanosphere self-assembly process is necessary to enable further development and scaling of this technology. The self-assembly of nanospheres into two-dimensional periodic arrays has previously been attributed solely to the Marangoni force; however, we demonstrate that the ζ potential of the nanosphere solution is critically important for successful self-assembly to occur. We discuss and demonstrate how this insight can be used to greatly increase self-assembled 2D periodic array areas while decreasing patterning time and cost. As a representative application, we fabricate antireflection nanostructures on a transparent flexible polymer substrate suitable for use as a large-area (270 cm), broadband, omnidirectional antireflection film.
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http://dx.doi.org/10.1021/acs.nanolett.0c01277DOI Listing
July 2020

Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance.

mBio 2020 05 26;11(3). Epub 2020 May 26.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

is an obligate human pathogen and causative agent of the sexually transmitted infection (STI) gonorrhea. The most predominant and clinically important multidrug efflux system in is the ultiple ransferrable esistance (Mtr) pump, which mediates resistance to a number of different classes of structurally diverse antimicrobial agents, including clinically used antibiotics (e.g., β-lactams and macrolides), dyes, detergents and host-derived antimicrobials (e.g., cationic antimicrobial peptides and bile salts). Recently, it has been found that gonococci bearing mosaic-like sequences within the gene can result in amino acid changes that increase the MtrD multidrug efflux pump activity, probably by influencing antimicrobial recognition and/or extrusion to elevate the level of antibiotic resistance. Here, we report drug-bound solution structures of the MtrD multidrug efflux pump carrying a mosaic-like sequence using single-particle cryo-electron microscopy, with the antibiotics bound deeply inside the periplasmic domain of the pump. Through this structural approach coupled with genetic studies, we identify critical amino acids that are important for drug resistance and propose a mechanism for proton translocation. has become a highly antimicrobial-resistant Gram-negative pathogen. Multidrug efflux is a major mechanism that uses to counteract the action of multiple classes of antibiotics. It appears that gonococci bearing mosaic-like sequences within the gene , encoding the most predominant and clinically important transporter of any gonococcal multidrug efflux pump, significantly elevate drug resistance and enhance transport function. Here, we report cryo-electron microscopy (EM) structures of MtrD carrying a mosaic-like sequence that allow us to understand the mechanism of drug recognition. Our work will ultimately inform structure-guided drug design for inhibiting these critical multidrug efflux pumps.
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http://dx.doi.org/10.1128/mBio.00996-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251214PMC
May 2020

Hyperspectral imaging for high-throughput, spatially resolved spectroscopic scatterometry of silicon nanopillar arrays.

Opt Express 2020 May;28(10):14209-14221

Modern high-throughput nanopatterning techniques, such as nanoimprint lithography, make it possible to fabricate arrays of nanostructures (features with dimensions of 10's to 100's of nm) over large area substrates (cm to m scale) such as Si wafers, glass sheets, and flexible roll-to-roll webs. The ability to make such large-area nanostructure arrays (LNAs) has created an extensive design space, enabling a wide array of applications including optical devices, such as wire-grid polarizers, transparent conductors, color filters, and anti-reflection surfaces, and building blocks for electronic components, such as ultracapacitors, sensors, and memory storage architectures. However, existing metrology methods will have trouble scaling alongside fabrication methods. Scanning electron microscopy (SEM) and atomic force microscopy (AFM), for instance, have micron scale fields of view (FOV) that preclude comprehensive characterization of LNAs, which may be manufactured at m per minute rates. Scatterometry approaches have larger FOVs (typically 100's of µm to a few mm), but traditional scatterometry systems measure samples one point at a time, which also makes them too slow for large-scale LNA manufacturing. In this work, we demonstrate parallelization of the traditional spectroscopic scatterometry approach using hyperspectral imaging, increasing the throughput of the technique by a factor of 10-10. We demonstrate this approach by using hyperspectral imaging and inverse modeling of reflectance spectra to derive 3-dimensional geometric data for Si nanopillar array structures over both mm and cm-scale with µm-scale spatial resolution. This work suggests that geometric measurements for a variety of LNAs can be performed with the potential for high speed over large areas which may be critical for future LNA manufacturing.
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http://dx.doi.org/10.1364/OE.388158DOI Listing
May 2020

Structure and function of LCI1: a plasma membrane CO channel in the Chlamydomonas CO concentrating mechanism.

Plant J 2020 06 18;102(6):1107-1126. Epub 2020 Apr 18.

Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA, 50011, USA.

Microalgae and cyanobacteria contribute roughly half of the global photosynthetic carbon assimilation. Faced with limited access to CO in aquatic environments, which can vary daily or hourly, these microorganisms have evolved use of an efficient CO concentrating mechanism (CCM) to accumulate high internal concentrations of inorganic carbon (C ) to maintain photosynthetic performance. For eukaryotic algae, a combination of molecular, genetic and physiological studies using the model organism Chlamydomonas reinhardtii, have revealed the function and molecular characteristics of many CCM components, including active C uptake systems. Fundamental to eukaryotic C uptake systems are C transporters/channels located in membranes of various cell compartments, which together facilitate the movement of C from the environment into the chloroplast, where primary CO assimilation occurs. Two putative plasma membrane C transporters, HLA3 and LCI1, are reportedly involved in active C uptake. Based on previous studies, HLA3 clearly plays a meaningful role in HCO transport, but the function of LCI1 has not yet been thoroughly investigated so remains somewhat obscure. Here we report a crystal structure of the full-length LCI1 membrane protein to reveal LCI1 structural characteristics, as well as in vivo physiological studies in an LCI1 loss-of-function mutant to reveal the C species preference for LCI1. Together, these new studies demonstrate LCI1 plays an important role in active CO uptake and that LCI1 likely functions as a plasma membrane CO channel, possibly a gated channel.
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http://dx.doi.org/10.1111/tpj.14745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305984PMC
June 2020

Pharyngeal-Cervico-Brachial/Miller Fisher Overlap Syndrome With Infliximab Exposure.

J Clin Neuromuscul Dis 2020 03;21(3):157-158

Staten Island University Hospital, Staten Island, New York, NY.

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http://dx.doi.org/10.1097/CND.0000000000000274DOI Listing
March 2020

Cryo-electron Microscopy Structure of the Acinetobacter baumannii 70S Ribosome and Implications for New Antibiotic Development.

mBio 2020 01 21;11(1). Epub 2020 Jan 21.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Antimicrobial resistance is a major health threat as it limits treatment options for infection. At the forefront of this serious issue is , a Gram-negative opportunistic pathogen that exhibits the remarkable ability to resist antibiotics through multiple mechanisms. As bacterial ribosomes represent a target for multiple distinct classes of existing antimicrobial agents, we here use single-particle cryo-electron microscopy (cryo-EM) to elucidate five different structural states of the ribosome, including the 70S, 50S, and 30S forms. We also determined interparticle motions of the 70S ribosome in different tRNA bound states using three-dimensional (3D) variability analysis. Together, our structural data further our understanding of the ribosome from and other Gram-negative pathogens and will enable structure-based drug discovery to combat antibiotic-resistant bacterial infections. is a severe nosocomial threat largely due to its intrinsic antibiotic resistance and remarkable ability to acquire new resistance determinants. The bacterial ribosome serves as a major target for modern antibiotics and the design of new therapeutics. Here, we present cryo-EM structures of the 70S ribosome, revealing several unique species-specific structural features that may facilitate future drug development to combat this recalcitrant bacterial pathogen.
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http://dx.doi.org/10.1128/mBio.03117-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974574PMC
January 2020

A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases.

Cureus 2019 Dec 16;11(12):e6394. Epub 2019 Dec 16.

Radiation Oncology, London Regional Cancer Program, London Health Sciences Centre, London, CAN.

Purpose/Objective Published preclinical and phase I clinical trial data suggest that fractionated lesional radiotherapy with 60 Gy in 10 fractions can serve as an alternative approach to single fraction radiosurgical boost for brain oligometastases.  Methods and Materials A phase II clinical trial (NCT01543542) of a total of 60 Gy in 10 fractions of lesional (one to three) radiotherapy (given simultaneously with whole-brain helical tomotherapy with 30 Gy in 10 fractions) was conducted at five institutions. We hypothesized that fractionated radiotherapy would be considered unsuitable if the median overall survival (OS) was degraded by two months or if six-month intracranial control (ICC) and intracranial lesion (ILC) were inferior by 10% compared with the published RTOG 9508 results. Results A total of 87 patients were enrolled over a 4.5-year accrual period. Radiological lesion and extralesional central nervous system progression were documented in 15/87 (17%) and 11/87 (13%) patients, respectively. Median OS for all patients was 5.4 months. Six-month actuarial estimates of ICC and ILC were 78% and 89%, respectively. However, only the ILC estimate achieved statistical significance (p=0.02), demonstrating non-inferiority to the a priori historical controls (OS: p=0.09, ICC=0.31). Two patients developed suspected asymptomatic radionecrosis. Conclusions The phase II estimates of ILC were demonstrated to be non-inferior to the results of the RTOG 9508.
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http://dx.doi.org/10.7759/cureus.6394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959838PMC
December 2019

Electrodeposition of crystalline silicon films from silicon dioxide for low-cost photovoltaic applications.

Nat Commun 2019 12 18;10(1):5772. Epub 2019 Dec 18.

Center for Electrochemistry, Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.

Crystalline-silicon solar cells have dominated the photovoltaics market for the past several decades. One of the long standing challenges is the large contribution of silicon wafer cost to the overall module cost. Here, we demonstrate a simple process for making high-purity solar-grade silicon films directly from silicon dioxide via a one-step electrodeposition process in molten salt for possible photovoltaic applications. High-purity silicon films can be deposited with tunable film thickness and doping type by varying the electrodeposition conditions. These electrodeposited silicon films show about 40 to 50% of photocurrent density of a commercial silicon wafer by photoelectrochemical measurements and the highest power conversion efficiency is 3.1% as a solar cell. Compared to the conventional manufacturing process for solar grade silicon wafer production, this approach greatly reduces the capital cost and energy consumption, providing a promising strategy for low-cost silicon solar cells production.
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http://dx.doi.org/10.1038/s41467-019-13065-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920409PMC
December 2019

Assessment of precision irradiation in early non-small cell lung cancer and interstitial lung disease (ASPIRE-ILD): study protocol for a phase II trial.

BMC Cancer 2019 Dec 11;19(1):1206. Epub 2019 Dec 11.

Department of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, V5Z 1M9, Canada.

Background: Stereotactic ablative radiotherapy (SABR) has become an established treatment option for medically-inoperable early-stage (Stage I-IIA) non-small cell lung cancer (ES-NSCLC). SABR is able to obtain high rates of local control with low rates of symptomatic toxicity in this patient population. However, in a subset of patients with fibrotic interstitial lung disease (ILD), elevated rates of SABR-related toxicity and mortality have been described. The Assessment of Precision Irradiation in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease (ASPIRE-ILD) study will conduct a thorough prospective evaluation of the clinical outcomes, toxicity, changes in diagnostic test parameters and patient-related outcomes following SABR for ES-NSCLC for patients with fibrotic ILD.

Methods: ASPIRE-ILD is a single-arm Phase II prospective study. The accrual target is 39 adult patients with T1-2N0M0 non-small cell lung cancer with co-existing ILD who are not candidates for surgical excision. Pathological confirmation of diagnosis is strongly recommended but not strictly required. Enrolled patients will be stratified by ILD-related mortality risk. The starting SABR dose will be 50 Gy in 5 fractions every other day (biologically effective dose: 100 Gy or 217 Gy), but the radiation dose can be de-escalated up to two times to 50 Gy in 10 fractions daily (75 Gy or 133 Gy) and 45 Gy in 15 fractions daily (58 Gy or 90 Gy). Dose de-escalation will occur if 2 or more of the first 7 patients in a cohort experiences grade 5 toxicity within 6 months of treatment. Similarly, dose de-escalation can also occur if 2 or more of the first 7 patients with a specific subtype of ILD experiences grade 5 toxicity within 6 months of treatment. The primary endpoint is overall survival. Secondary endpoints include toxicity (CTC-AE 4.0), progression-free survival, local control, patient-reported outcomes (cough severity and quality of life), rates of ILD exacerbation and changes in pulmonary function tests/high-resolution computed tomography findings post-SABR.

Discussion: ASPIRE-ILD will be the first prospective study specifically designed to comprehensively evaluate the effectiveness and safety of SABR for ES-NSCLC in patients with co-existing ILD.

Trial Registration: Clinicaltrials.gov identifier: NCT03485378. Date of registration: April 2, 2018.
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http://dx.doi.org/10.1186/s12885-019-6392-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905060PMC
December 2019

Structural and functional evidence that lipoprotein LpqN supports cell envelope biogenesis in .

J Biol Chem 2019 10 30;294(43):15711-15723. Epub 2019 Aug 30.

Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon 97239

The mycobacterial cell envelope is crucial to host-pathogen interactions as a barrier against antibiotics and the host immune response. In addition, cell envelope lipids are mycobacterial virulence factors. Cell envelope lipid biosynthesis is the target of a number of frontline tuberculosis treatments and has been the focus of much research. However, the transport mechanisms by which these lipids reach the mycomembrane remain poorly understood. Many envelope lipids are exported from the cytoplasm to the periplasmic space via the mycobacterial membrane protein large (MmpL) family of proteins. In other bacteria, lipoproteins can contribute to outer membrane biogenesis through direct binding of substrates and/or protein-protein associations with extracytoplasmic biosynthetic enzymes. In this report, we investigate whether the lipoprotein LpqN plays a similar role in mycobacteria. Using a genetic two-hybrid approach, we demonstrate that LpqN interacts with periplasmic loop domains of the MmpL3 and MmpL11 transporters that export mycolic acid-containing cell envelope lipids. We observe that LpqN also interacts with secreted cell envelope biosynthetic enzymes such as Ag85A via pulldown assays. The X-ray crystal structures of LpqN and LpqN bound to dodecyl-trehalose suggest that LpqN directly binds trehalose monomycolate, the MmpL3 and Ag85A substrate. Finally, we observe altered lipid profiles of the Δ mutant during biofilm maturation, pointing toward a possible physiological role for the protein. The results of this study suggest that LpqN may act as a membrane fusion protein, connecting MmpL transporters with periplasmic proteins, and provide general insight into the role of lipoproteins in cell envelope biogenesis.
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http://dx.doi.org/10.1074/jbc.RA119.008781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816100PMC
October 2019

Phase III Randomized Pair Comparison of a Barrier Film vs. Standard Skin Care in Preventing Radiation Dermatitis in Post-lumpectomy Patients with Breast Cancer Receiving Adjuvant Radiation Therapy.

Cureus 2019 Jun 3;11(6):e4807. Epub 2019 Jun 3.

Radiation Oncology, Schulich School of Medicine and Dentistry, Western University, London, CAN.

Introduction Patients undergoing adjuvant radiotherapy to the breast often experience radiation dermatitis ranging from mild erythema to moist desquamation. In post-lumpectomy patients, the axilla and inframammary fold are at an increased risk for friction dermatitis. Dermatitis can impact patients' quality-of-life and may require treatment break/cessation. Our objectives are to assess the efficacy of 3M Cavilon Barrier Film (BF) in preventing and/or delaying the onset of grade-two dermatitis and reducing patient-reported sensation scores. Methods A total of 55 patients were randomized to receive BF on the medial or lateral breast. BF was applied twice weekly during treatment. Skin toxicity was evaluated weekly by a blinded clinical investigator using the Skin Toxicity Assessment Tool (STAT) and the modified Radiation Therapy Oncology Group Visual Assessment Score (RTOG VAS). On day one, baseline photographs were taken; seven-to-ten days post-treatment, patients returned for photographs, the STAT/RTOG VAS, and patient-opinion questions in the form of the global questionnaire. Results The paired analysis found BF did not significantly reduce dermatitis either during or post-treatment. However, the unpaired analysis found significantly reduced RTOG VAS on the lateral compartment during treatment (BF:0.91 vs. Control:1.21, = 0.0408). This difference resolved post-treatment. Additionally, BF was able to reduce pruritus ( = 0.047) on the medial components and burning sensations on the lateral components ( = 0.035). There was no significant difference between the time-to-onset or proportion of patients who developed grade-two dermatitis. Conclusion In an unpaired analysis, BF significantly reduced dermatitis on the lateral compartment during treatment. Additionally, BF significantly reduced pruritus and burning sensations. A larger study using a more reliable scoring method is required to clarify the effect of BF on radiation-associated skin toxicity.
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http://dx.doi.org/10.7759/cureus.4807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682394PMC
June 2019

Plasma Metabolites Associated with Frequent Red Wine Consumption: A Metabolomics Approach within the PREDIMED Study.

Mol Nutr Food Res 2019 09 17;63(17):e1900140. Epub 2019 Jul 17.

Human Nutrition Unit, Faculty of Medicine and Health Sciences, Sant Joan Hospital, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, 43201, Reus, Spain.

Scope: The relationship between red wine (RW) consumption and metabolism is poorly understood. It is aimed to assess the systemic metabolomic profiles in relation to frequent RW consumption as well as the ability of a set of metabolites to discriminate RW consumers.

Methods And Results: A cross-sectional analysis of 1157 participants is carried out. Subjects are divided as non-RW consumers versus RW consumers (>1 glass per day RW [100 mL per day]). Plasma metabolomics analysis is performed using LC-MS. Associations between 386 identified metabolites and RW consumption are assessed using elastic net regression analysis taking into consideration baseline significant covariates. Ten-cross-validation (CV) is performed and receiver operating characteristic curves are constructed in each of the validation datasets based on weighted models. A subset of 13 metabolites is consistently selected and RW consumers versus nonconsumers are discriminated. Based on the multi-metabolite model weighted with the regression coefficients of metabolites, the area under the curve is 0.83 (95% CI: 0.80-0.86). These metabolites mainly consisted of lipid species, some organic acids, and alkaloids.

Conclusions: A multi-metabolite model identified in a Mediterranean population appears useful to discriminate between frequent RW consumers and nonconsumers. Further studies are needed to assess the contribution of these metabolites in health and disease.
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http://dx.doi.org/10.1002/mnfr.201900140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771435PMC
September 2019

Cryo-Electron Microscopy Structure of an Acinetobacter baumannii Multidrug Efflux Pump.

mBio 2019 07 2;10(4). Epub 2019 Jul 2.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Resistance-nodulation-cell division multidrug efflux pumps are membrane proteins that catalyze the export of drugs and toxic compounds out of bacterial cells. Within the hydrophobe-amphiphile subfamily, these multidrug-resistant proteins form trimeric efflux pumps. The drug efflux process is energized by the influx of protons. Here, we use single-particle cryo-electron microscopy to elucidate the structure of the AdeB multidrug efflux pump embedded in lipidic nanodiscs to a resolution of 2.98 Å. We found that each AdeB molecule within the trimer preferentially takes the resting conformational state in the absence of substrates. We propose that proton influx and drug efflux are synchronized and coordinated within the transport cycle. is a successful human pathogen which has emerged as one of the most problematic and highly antibiotic-resistant Gram-negative bacteria worldwide. Multidrug efflux is a major mechanism that uses to counteract the action of multiple classes of antibiotics, such as β-lactams, tetracyclines, fluoroquinolones, and aminoglycosides. Here, we report a cryo-electron microscopy (cryo-EM) structure of the prevalent AdeB multidrug efflux pump, which indicates a plausible pathway for multidrug extrusion. Overall, our data suggest a mechanism for energy coupling that powers up this membrane protein to export antibiotics from bacterial cells. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.
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http://dx.doi.org/10.1128/mBio.01295-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606808PMC
July 2019

MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine.

Proc Natl Acad Sci U S A 2019 06 21;116(23):11241-11246. Epub 2019 May 21.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;

The cell envelope of is notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure of MmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.
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http://dx.doi.org/10.1073/pnas.1901346116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561238PMC
June 2019

Plasma Metabolites Associated with Coffee Consumption: A Metabolomic Approach within the PREDIMED Study.

Nutrients 2019 May 8;11(5). Epub 2019 May 8.

Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, 43201 Reus, Spain.

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (≥50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56-0.64), 0.78 (95% CI 0.75-0.81) and 0.52 (95% CI 0.49-0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption.
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http://dx.doi.org/10.3390/nu11051032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566346PMC
May 2019

Complete Occlusion of Bilateral Internal Carotid Artery in a Marijuana Smoker: A Case Report.

J Clin Med Res 2019 Apr 18;11(4):305-308. Epub 2019 Mar 18.

Department of Neurology, Staten Island University Hospital, Staten Island, NY 10305, USA.

Here we described a case of a young male who developed stroke attributable to heavy marijuana smoking. Although, instances of stroke due to cannabis smoking have been reported earlier, this case is distinctive due to the fact that the patient had bilateral complete occlusion of internal carotid artery (ICA) at a very early age. In view of studies that have correlated marijuana smoking to intracranial stenosis and atherogenesis, this case of bilateral ICA occlusion illustrates the severity and burden of the disease.
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http://dx.doi.org/10.14740/jocmr3132wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436573PMC
April 2019

Metabolites related to purine catabolism and risk of type 2 diabetes incidence; modifying effects of the TCF7L2-rs7903146 polymorphism.

Sci Rep 2019 02 27;9(1):2892. Epub 2019 Feb 27.

Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain.

Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid ratio and high xanthine-to-hypoxanthine ratio were inversely and positively associated with T2D risk, respectively, independently of classical risk factors. Elevated plasma xanthine and inosine levels were associated with a higher T2D risk in homozygous carriers of the TCF7L2-rs7903146 T-allele. The potential mechanisms linking the aforementioned purine metabolites and T2D risk must be also further investigated.
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http://dx.doi.org/10.1038/s41598-019-39441-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393542PMC
February 2019

Plasma metabolites predict both insulin resistance and incident type 2 diabetes: a metabolomics approach within the Prevención con Dieta Mediterránea (PREDIMED) study.

Am J Clin Nutr 2019 03;109(3):626-634

Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain.

Background: Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D).

Objectives: The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D.

Methods: We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models.

Results: We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors.

Conclusions: The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D.
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http://dx.doi.org/10.1093/ajcn/nqy262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307433PMC
March 2019
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